Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)
The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-yl)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or...
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| Veröffentlicht in: | Journal of medicinal chemistry 2011-04, Vol.54 (7), p.2266-2281 |
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| container_title | Journal of medicinal chemistry |
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| creator | Whitby, Richard J Stec, Jozef Blind, Raymond D Dixon, Sally Leesnitzer, Lisa M Orband-Miller, Lisa A Williams, Shawn P Willson, Timothy M Xu, Robert Zuercher, William J Cai, Fang Ingraham, Holly A |
| description | The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-yl)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure−activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes. |
| doi_str_mv | 10.1021/jm1014296 |
| format | Article |
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Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm1014296</identifier><identifier>PMID: 21391689</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>60 APPLIED LIFE SCIENCES ; Amino Acid Sequence ; ANIMAL CELLS ; Animals ; BASIC BIOLOGICAL SCIENCES ; CRYSTAL STRUCTURE ; Crystallography, X-Ray ; GENES ; HEK293 Cells ; Humans ; Ligands ; LIVER ; Mice ; Models, Molecular ; Molecular Sequence Data ; PEPTIDES ; Protein Conformation ; Receptors, Cytoplasmic and Nuclear - agonists ; Receptors, Cytoplasmic and Nuclear - chemistry ; Receptors, Cytoplasmic and Nuclear - metabolism ; REGULATIONS ; Sequence Homology, Amino Acid ; Small Molecule Libraries - chemical synthesis ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - pharmacology ; Steroidogenic Factor 1 - agonists ; Steroidogenic Factor 1 - chemistry ; Steroidogenic Factor 1 - metabolism ; TARGETS ; Transcriptional Activation - drug effects</subject><ispartof>Journal of medicinal chemistry, 2011-04, Vol.54 (7), p.2266-2281</ispartof><rights>Copyright © 2011 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a497t-92f6e353e90bee76a527a06690d28f9f662d12f5f1c5cb53a541d9cd8b3a0ec03</citedby><cites>FETCH-LOGICAL-a497t-92f6e353e90bee76a527a06690d28f9f662d12f5f1c5cb53a541d9cd8b3a0ec03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm1014296$$EPDF$$P50$$Gacs$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm1014296$$EHTML$$P50$$Gacs$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21391689$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1025640$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Whitby, Richard J</creatorcontrib><creatorcontrib>Stec, Jozef</creatorcontrib><creatorcontrib>Blind, Raymond D</creatorcontrib><creatorcontrib>Dixon, Sally</creatorcontrib><creatorcontrib>Leesnitzer, Lisa M</creatorcontrib><creatorcontrib>Orband-Miller, Lisa A</creatorcontrib><creatorcontrib>Williams, Shawn P</creatorcontrib><creatorcontrib>Willson, Timothy M</creatorcontrib><creatorcontrib>Xu, Robert</creatorcontrib><creatorcontrib>Zuercher, William J</creatorcontrib><creatorcontrib>Cai, Fang</creatorcontrib><creatorcontrib>Ingraham, Holly A</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-yl)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure−activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Amino Acid Sequence</subject><subject>ANIMAL CELLS</subject><subject>Animals</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>CRYSTAL STRUCTURE</subject><subject>Crystallography, X-Ray</subject><subject>GENES</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Ligands</subject><subject>LIVER</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>PEPTIDES</subject><subject>Protein Conformation</subject><subject>Receptors, Cytoplasmic and Nuclear - agonists</subject><subject>Receptors, Cytoplasmic and Nuclear - chemistry</subject><subject>Receptors, Cytoplasmic and Nuclear - metabolism</subject><subject>REGULATIONS</subject><subject>Sequence Homology, Amino Acid</subject><subject>Small Molecule Libraries - chemical synthesis</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Steroidogenic Factor 1 - agonists</subject><subject>Steroidogenic Factor 1 - chemistry</subject><subject>Steroidogenic Factor 1 - metabolism</subject><subject>TARGETS</subject><subject>Transcriptional Activation - drug effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>N~.</sourceid><sourceid>EIF</sourceid><recordid>eNpt0dGKEzEUBuAgiltXL3wBCYJgwdGcZJI2N0JZrF2ou9DqdUgzZ9opM0lJMgv7CvvUTqlbFfYqkHz5E85PyFtgn4Fx-LLvgEHJtXpGRiA5K8opK5-TEWOcF1xxcUFepbRnjAng4iW54CA0qKkekYd1Z9uW_ggtur5FOtsG36ScaKhp3iG9jYed9fSmdy3aSFfo8JBDTHSdMYamClv0jaNz64bdAujH9byAT_RmJWcwptZXdNnc4d-LdBG60IZtj0e8XC0eNR-_Ji9q2yZ882e9JL_m335eLYrl7ffrq9mysKWe5ELzWqGQAjXbIE6UlXximVKaVXxa61opXgGvZQ1Ouo0UVpZQaVdNN8IydExckq-n3EO_6bBy6HO0rTnEprPx3gTbmP9PfLMz23BnSpDH6Q4B708BIeXGJNdkdDsXvEeXzVCIVOURjU_IxZBSxPr8ALAjAnNubbDv_v3RWT7WNIAPJ2BdMvvQRz8M6Img3_G8m8o</recordid><startdate>20110414</startdate><enddate>20110414</enddate><creator>Whitby, Richard J</creator><creator>Stec, Jozef</creator><creator>Blind, Raymond D</creator><creator>Dixon, Sally</creator><creator>Leesnitzer, Lisa M</creator><creator>Orband-Miller, Lisa A</creator><creator>Williams, Shawn P</creator><creator>Willson, Timothy M</creator><creator>Xu, Robert</creator><creator>Zuercher, William J</creator><creator>Cai, Fang</creator><creator>Ingraham, Holly A</creator><general>American Chemical Society</general><scope>N~.</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>OTOTI</scope><scope>5PM</scope></search><sort><creationdate>20110414</creationdate><title>Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)</title><author>Whitby, Richard J ; Stec, Jozef ; Blind, Raymond D ; Dixon, Sally ; Leesnitzer, Lisa M ; Orband-Miller, Lisa A ; Williams, Shawn P ; Willson, Timothy M ; Xu, Robert ; Zuercher, William J ; Cai, Fang ; Ingraham, Holly A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a497t-92f6e353e90bee76a527a06690d28f9f662d12f5f1c5cb53a541d9cd8b3a0ec03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Amino Acid Sequence</topic><topic>ANIMAL CELLS</topic><topic>Animals</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>CRYSTAL STRUCTURE</topic><topic>Crystallography, X-Ray</topic><topic>GENES</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Ligands</topic><topic>LIVER</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>PEPTIDES</topic><topic>Protein Conformation</topic><topic>Receptors, Cytoplasmic and Nuclear - agonists</topic><topic>Receptors, Cytoplasmic and Nuclear - chemistry</topic><topic>Receptors, Cytoplasmic and Nuclear - metabolism</topic><topic>REGULATIONS</topic><topic>Sequence Homology, Amino Acid</topic><topic>Small Molecule Libraries - chemical synthesis</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Small Molecule Libraries - pharmacology</topic><topic>Steroidogenic Factor 1 - agonists</topic><topic>Steroidogenic Factor 1 - chemistry</topic><topic>Steroidogenic Factor 1 - metabolism</topic><topic>TARGETS</topic><topic>Transcriptional Activation - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Whitby, Richard J</creatorcontrib><creatorcontrib>Stec, Jozef</creatorcontrib><creatorcontrib>Blind, Raymond D</creatorcontrib><creatorcontrib>Dixon, Sally</creatorcontrib><creatorcontrib>Leesnitzer, Lisa M</creatorcontrib><creatorcontrib>Orband-Miller, Lisa A</creatorcontrib><creatorcontrib>Williams, Shawn P</creatorcontrib><creatorcontrib>Willson, Timothy M</creatorcontrib><creatorcontrib>Xu, Robert</creatorcontrib><creatorcontrib>Zuercher, William J</creatorcontrib><creatorcontrib>Cai, Fang</creatorcontrib><creatorcontrib>Ingraham, Holly A</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><collection>American Chemical Society (ACS) Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Whitby, Richard J</au><au>Stec, Jozef</au><au>Blind, Raymond D</au><au>Dixon, Sally</au><au>Leesnitzer, Lisa M</au><au>Orband-Miller, Lisa A</au><au>Williams, Shawn P</au><au>Willson, Timothy M</au><au>Xu, Robert</au><au>Zuercher, William J</au><au>Cai, Fang</au><au>Ingraham, Holly A</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2011-04-14</date><risdate>2011</risdate><volume>54</volume><issue>7</issue><spage>2266</spage><epage>2281</epage><pages>2266-2281</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-yl)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure−activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>21391689</pmid><doi>10.1021/jm1014296</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2011-04, Vol.54 (7), p.2266-2281 |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | 60 APPLIED LIFE SCIENCES Amino Acid Sequence ANIMAL CELLS Animals BASIC BIOLOGICAL SCIENCES CRYSTAL STRUCTURE Crystallography, X-Ray GENES HEK293 Cells Humans Ligands LIVER Mice Models, Molecular Molecular Sequence Data PEPTIDES Protein Conformation Receptors, Cytoplasmic and Nuclear - agonists Receptors, Cytoplasmic and Nuclear - chemistry Receptors, Cytoplasmic and Nuclear - metabolism REGULATIONS Sequence Homology, Amino Acid Small Molecule Libraries - chemical synthesis Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Steroidogenic Factor 1 - agonists Steroidogenic Factor 1 - chemistry Steroidogenic Factor 1 - metabolism TARGETS Transcriptional Activation - drug effects |
| title | Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2) |
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